Formulations Containing an Ionic Mineral-Ion Exchange Resin Complex and Uses Thereof

ABSTRACT

A process for preparing a formulation comprising a complex comprising an effective amount of ferrous iron bound to a pharmaceutically acceptable cationic resin and at least one pharmaceutically acceptable carrier is described. Such a formulation may optionally include other desirable dietary supplements including, e.g., vitamins, omega fatty acids, and/or fluoride. The formulation is particularly well adapted for pediatric use, but is also useful for use in adult populations.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.12/441,918, filed Mar. 19, 2009, which is a national stage pursuant to35 USC 371 of PCT/US2007/020844, filed Sep. 27, 2007, which claimed thebenefit under 35 USC 119(e) of U.S. patent application Ser. No.60/827,974, filed Oct. 3, 2006, now expired.

BACKGROUND OF THE INVENTION

The present invention relates to a formulation having a mineral-ionexchange resin complex that is useful as a dietary supplement.

A variety of commercial products are available which have been describedas being useful as dietary supplements and/or for treatment of certainmineral and vitamin deficiencies. Such products have been formulated foreither pediatric delivery (infants and children) or for adults(including the geriatric population). Depending upon the targetpopulation, such products are available as liquid suspensions, powders,tablets and/or other solid forms. Certain of these products, including,notably, those containing iron supplements in liquid faun, have beenreported to have undesirable side effects including, e.g., gastricirritation and stomach upset, staining of teeth, and a less thandesirable taste. See, e.g., side effects listed on product label forFer-In-Sol® iron supplement [Mead Johnson], “Pharmacy and TherapeuticsCommittee Medication Review, May 21, 2004, citing Drug Facts andComparisons, updated Nov. 2003.

Use of ion-exchange resins to form a drug - ion exchange resin complexis well known and is described, for example, in U.S. Pat. No. 2,990,332.In the '332 patent, the use of an ion-exchange resin to form a complexwith ionic drugs and thereby delay the drug release from such complexesis described. Such delay in drug release was deemed to be of relativelyshort duration. Since then there have been additional publications andpatents (e.g., U.S. Pat. Nos. 3,138,525; 3,499,960; 3,594,470; Belgianpatent 729,827; German patent 2,246,037) that describe use of suchion-exchange resin complexes with water-permeable diffusion barriercoatings of the drug-ion exchange resin complex coated to alter therelease of drugs from the drug-ion exchange resin complex. Ion-exchangeresin complexes have also been described by their manufacturers and inthe literature as being useful for taste masking of unpleasant tastingdrugs [Rohm and Haas].

Additionally, analysis of the iron state in some iron-containingvitamins and dietary supplements has revealed higher amounts of ferricimpurities than is desirable or permitted under FDA standards. See,Oshtrack et al, Analytica Chimica Acta, 506 (2004) 155-160. This articlereports that due to concerns regarding toxicity of ferric iron, the FDAhas indicated the ferrous fumarate dietary supplements should notcontain more than 2% ferric iron. The article also reports that severalmarketed formulations tested off the shelf have been found to havehigher ferric contents that permitted by the FDA due to oxidation.

Alternatives to the formulations currently on the market for dietarysupplements are desirable.

SUMMARY OF THE INVENTION

In one aspect, a method of manufacture of liquid suspensions comprisingionic mineral-ion exchange resin complexes is provided that reducesoxidation of the ionic mineral and improves yield. The method permitsformation of the final liquid suspension in the same vessel as the ionicmineral-ion exchange complex is formed, without requiring isolationthereof.

In another aspect, a non-toxic, orally ingestible mineral-ion exchangeresin formulation useful as a dietary supplement is provided. Theformulation comprises a complex comprising an effective amount of anionic mineral bound to a pharmaceutically acceptable ion exchange resin;and at least one pharmaceutically acceptable carrier.

In another aspect, the invention provides a formulation contains acomplex comprising an effective amount of ferrous iron bound to apharmaceutically acceptable cationic resin and at least onepharmaceutically acceptable carrier. Suitably, the formulation furthercomprises an antioxidant. In one embodiment, the composition isformulated for pediatric use.

In yet another aspect, the invention provides a composition comprising(a) non-toxic, orally ingestible mineral-ion exchange resin complexcomprising an effective amount of an ionic mineral bound to apharmaceutically acceptable ion exchange resin; (b) a vitamin; (c) afluoride compound; and (d) at least one pharmaceutically acceptablecarrier.

In still another aspect, the invention provides a method of deliveringan ionic mineral to a subject, via the ionic mineral-ion exchange resincomplex of the invention.

In yet a further aspect, the invention provides a method of treatingiron deficiency comprising the step of administering an effective amountof a non-toxic, orally ingestible iron-ion exchange resin formulationcomprising a complex comprising a pharmaceutically effective amount ofan ionic mineral component bound to a pharmaceutically acceptable ionexchange resin, and a pharmaceutically acceptable carrier.

The invention advantageously provides a reduction of undesirable tastessometimes associated with an orally ingestible vitamin formulation,where unpleasant taste of the ionic mineral may be a detriment forcompliance with the recommended daily intake.

Still other aspects and advantages of the invention will be readilyapparent from the following detailed description.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides an ionic mineral-ion exchange resinformulation useful for delivery to a subject as a dietary supplement, orfor therapeutic or prophylactic purposes. The formulation contains acomplex comprising an effective amount of an ionic mineral bound to apharmaceutically acceptable ion exchange resin; and at least onepharmaceutically acceptable carrier.

As used herein, “an effective amount” refers to an amount of acomponent, e.g., an ionic mineral, which provides a nutritional orpharmaceutical benefit to the subject to which it is administered in asingle or multiple units.

The term “ionic mineral” refers to an element or electrolyte, whichcarries a positive or negative charge. Desirably, the ionic mineralsdescribed herein are those which are useful for the functioning of thebody's cells. In one embodiment, the ionic mineral is iron. Otherexamples of such ionic minerals include, e.g., sodium, potassium,calcium, magnesium, chloride, and phosphate. These minerals are calledmacrominerals, since large quantities are required by the body. The bodyalso needs small quantities of copper, fluoride, iodine, iron, selenium,and zinc. These minerals are called trace minerals. Someminerals—especially the macrominerals—are important as electrolytes. Thebody uses electrolytes to help regulate nerve and muscle function andacid-base balance. Also, electrolytes help the body maintain normalvolume in its different fluid-containing areas (compartments). Otherionic minerals include, without limitation, boron, chromium, cobalt,germanium, gold, nickel, silver, iodine, molybdenum, platinum, sulfur,tin, vandadium. Still other suitable ionic minerals will be readilyapparent to one of skill in the art. For example, one may select lithiumfor inclusion in a resin complex as described herein.

Suitably, the source of the ionic mineral is a compound which containsthe ionic mineral bound or complexed to a moiety from which it readilydissociates in a non-ionic, physiologically compatible diluent so as topermit the ionic mineral to bind to the ionic resin and which isdissociated from a donor element or moiety which is not physiologicallydetrimental or incompatible with other components of the suspension.Optionally, the freed moiety may itself be physiologically useful (e.g.,a sulfur compound). Suitable compounds can be found in the scientificliterature; additionally, many such compounds are commerciallyavailable. Examples of suitable compounds include a salt, such as asulfate, a carbonate, an ascorbate, a citrate, or the like, of the ionicmolecule, may be readily selected. Alternatively, the ionic mineral maybe bound to another salt or another moiety. For example, if the ionicmineral is iron, the source of the compound is desirably ferroussulfate, which readily dissociates and which provides freed sulfate.However, other donor sources of iron may be readily selected including,e.g., a ferrous fumarate, a polymaltose, a bisglycinate, ferrous glycinesulphate, ferrous gluconate, ferrous citrate, ferrous carbonate, ferrouslactate, ferrous succinate, ferrous ascorbate, an amino acid ferrouscomplex, or a hydrate thereof. Donor sources for other ionic mineralsincluding, e.g., ferric iron or another ionic mineral described herein,will be readily apparent to one of skill in the art.

Suitable dietary intakes for various minerals and vitamins can bereadily obtained from the Food and Nutrition Board of the NationalAcademy of Sciences, taking into consideration whether the targetpopulation is pediatric or adult and other relevant factors within theadult population, including, gender, pregnancy, lactating, over 51. Forexample, for iron, recommended daily amounts are:

Age (years) or status RDA mg/day 0.0 to 0.5 6 0.5 to 1.0 10 1 to 3 10 4to 6 10  7-10 10 Males Females 11-14 12 15 15-18 12 15 19-24 10 15 25-5010 15 51 and over 10 10 Pregnant — 30 Lactating — 15

Guidelines are also provided for the dietary reference intakes availablefrom the Food and Nutrition Board for elements, e.g., calcium, chromium,magnesium, phosphorus, fluoride, manganese, zinc, selenium, electrolytesincluding, e.g., sodium, potassium, and inorganic sulfate, and vitaminsincluding, e.g., Vitamin A, Vitamin C, Vitamin D, Vitamin B₃ [known asniacin, and also available as nicotinic acid and pharmaceuticallyacceptable salts thereof], Vitamin B₆, Vitamin B₁₂, Vitamin E andVitamin K. Other desirable nutrient components for dietary supplementsmay include folate, (or its synthetic form, folic acid, orpharmaceutically acceptable salts thereof), and omega-3-fatty acids.

As used herein in reference to numeric values provided herein, the term“about” may indicate a variability of as much as ±10%.

Ion-Exchange Resin

Contemplated within the scope of the invention are important nutrientsand pharmaceutically active compounds safe for ingestion, which form acomplex with an ion-exchange resin and are manufactured in accordancewith Good Manufacturing Practices (GMP) for bulk pharmaceuticalchemicals. Typically, these compounds are designed for oraladministration and administration via a gastric and/or nasogastric tube.

Ion-exchange resins suitable for use in these preparations arewater-insoluble and comprise a preferably pharmacologically inertorganic and/or inorganic matrix containing functional groups that areionic or capable of being ionized under the appropriate conditions ofpH. The organic matrix may be synthetic (e.g., polymers or copolymers ofacrylic acid, methacrylic acid, sulfonated styrene, sulfonateddivinylbenzene), or partially synthetic (e.g. modified cellulose anddextrans). The inorganic matrix preferably comprises silica gel modifiedby the addition of ionic groups. Covalently bound ionic groups may bestrongly acidic (e.g., sulfonic acid, phosphoric acid), weakly acidic(e.g., carboxylic acid), strongly basic (e.g., primary amine), weaklybasic (e.g. quaternary ammonium), or a combination of acidic and basicgroups. In general, the types of ion exchangers suitable for use inion-exchange chromatography and for such applications as deionization ofwater are suitable for use in the controlled release of drugpreparations. Such ion-exchangers are described by H. F. Walton in“Principles of Ion Exchange” (pp: 312-343) and “Techniques andApplications of Ion-Exchange Chromatography” (pp: 344-361) inChromatography. (E. Heftmann, editor), van Nostrand Reinhold Company,New York (1975). Ion exchange resins that can be used in the presentinvention have exchange capacities of about 6 milliequivalents(meq)/gram and preferably about 5.5 meq/gram or below.

Typically the size of the ion-exchange particles is from about 1 micronto about 900 microns, in another embodiment, about 5 microns to 750microns, and in yet another embodiment, the particle size is within therange of about 40 microns to about 250 microns for liquid dosage formsalthough particles up to about 1,000 micron can be used for solid dosageforms, e.g., tablets and capsules. Particle sizes substantially belowthe lower limit are generally difficult to handle in all steps of theprocessing.

Both regularly and irregularly shaped particles may be used as resins.Regularly shaped particles are those particles that substantiallyconform to geometric shapes such as spherical, elliptical, cylindricaland the like, which are exemplified by Dow XYS-40010.00 and DowXYS-40013.00 (The Dow Chemical Company). Irregularly shaped particlesare all particles not considered to be regularly shaped, such asparticles with amorphous shapes and particles with increased surfaceareas due to surface channels or distortions. Irregularly shapedion-exchange resins of this type are exemplified by Amberlite IRP-69(Rohm and Haas). Two of the preferred resins useful in this inventionare Amberlite IRP-69 and Dow XYS-40010.00. Both are sulfonated polymerscomposed of polystyrene cross-linked with about 8% of divinylbenzene,with an ion-exchange capacity of about 4.5 to 5.5 meq/g of dry resin(H⁺-form). Their essential difference is in physical form. AmberliteIRP-69 consists of irregularly shaped particles with a size range ofabout 5 microns to about 149 microns produced by milling the parentlarge size spheres of Amberlite IRP-120. The Dow XYS-40010.00 productconsists of spherical particles with a size range of 45 microns to 150microns. Other suitable ion-exchange resins include anion exchangeresins, such as have been described in the art and are commerciallyavailable.

Cation exchange resins, e.g., AMBERLITE IRP-69, Amberlite IRP-64,Amberlite IRP-88 (Rohm & Haas), Dowex 50W resin (Dow), C100MR, C100HMR,C115KMR (Purolite), are particularly well suited for use with cationicminerals and other molecules having a cationic functionality, including,e.g., ferrous iron, ferric iron, potassium, sodium, calcium, lithium,zinc, magnesium, and selenium (in certain embodiments) as well asprodrugs, salts, isomers, polymorphs, and solvates thereof, as well asother minerals identified herein and/or known in the art. Cationicexchange resins are readily selected for use of these cationic mineralsidentified herein and/or are those which are known to those of skill inthe art.

Selenium has been described as having a valence of +2 or −2 dependingupon whether it is present as selenium (+2) (e.g., a selenium dioxide,selenic acid, selenous acid, selenium sulfide) or a selenite or selenide(e.g., sodium selenite, zinc selenide). Depending upon the source donorcompound, selenium may be complexed with a cationic exchange resin(e.g., if selenium dioxide is the source compound), or with an anionicexchange resin (e.g., if sodium selenite) is the source compound.

Anion exchange resins are useful in conjunction with anionic minerals,e.g., certain embodiments of selenium. An example of an anion exchangeresin is a cholestyramine resin, a strong base type 1 anion exchangeresin powder with a polystyrene matrix and quarternary ammoniumfunctional groups. The exchangeable anion is generally chloride whichcan be exchanged for, or replaced by, virtually any anionic species. Acommercially available Cholestyramine resins is PUROLITE™ A430MR resin.As described by its manufacturer, this resin has an average particlesize range of less than 150 microns, a pH in the range of 4-6, and anexchange capacity of 1.8-2.2 eq/dry gm. Another pharmaceutical gradecholestyramine resin is available as DUOLITE™ AP143/1094 [Rohm andHaas], described by the manufacturer as having a particle size in therange of 95%, less than 100 microns and 40%, less than 50 microns. Thecommercial literature from the suppliers of these and other resin isincorporated herein by reference (PUROLITE A-430 MR; DOW CholestyramineUSP, Form No. 177-01877-204, Dow Chemical Company; DUOLITE AP143/1083,Rohm and Haas Company, IE-566EDS—February 6).

The selected ion-exchange resins may be further treated by themanufacturer or the purchaser to maximize the safety for pharmaceuticaluse or for improved performance of the compositions Impurities presentin the resins may be removed or neutralized by the use of commonchelating agents, anti-oxidants, preservatives such as disodium edetate,sodium bisulfite, and so on by incorporating them at any stage ofpreparation either before complexation or during complexation orthereafter. These impurities along with their chelating agent to whichthey have bound may be removed before further treatment of the ionexchange resin

Ionic Mineral-Ion Exchange Resin Complexes

Binding of the selected ionic mineral(s) or combination of ionicmineral(s) and another component to the ion exchange resin can beaccomplished using methods known in the art. Typically the ionicmineral-ion exchange resin complex thus formed is collected byfiltration and washed with appropriate solvents to remove any ionicmineral or by-products. The complexes can be air-dried in trays, in afluid bed dryer, or other suitable dryer, at room temperature or atelevated temperature.

For preparing the complexes, the batch equilibration is the preferredpractice when loading a ionic mineral into finely divided ion exchangeresin powders. Due to its fine particle size, ion exchange resin doesnot lend itself to conventional columnar operations used with ionexchange resins. The total ion exchange capacity represents the maximumachievable capacity for exchanging cations or anions measured underideal laboratory conditions. The capacity which will be realized whenloading an ionic mineral onto ion exchange resin will be influenced bysuch factors as the inherent selectivity of the ion exchange resin forthe ionic mineral, the ionic mineral's concentration in the loadingsolution and the concentration of competing ions also present in theloading solution. The rate of loading will be affected by the activityof the ionic mineral and its molecular dimensions as well as the extentto which the polymer phase is swollen during loading.

When utilizing a batch or equilibrium process for loading an ionicmineral onto an ion exchange resin, it is usually desirable to load asmuch as possible of the substance of value onto the ion exchange resin.Complete transfer of the ionic mineral from the loading solution is notlikely in a single equilibrium stage. Accordingly, more than oneequilibration may be required in order to achieve the desired loadingonto the ion exchange resin. The use of two or more loading stages,separating the resin from the liquid phase between stages, is a means ofachieving maximum loading of the ionic mineral onto the ion exchangeresin although loss of ionic mineral from the liquid phase of the finalstage occurs.

Although carefully controlled laboratory experiments are required toestablish precise loading and elution conditions, a few generalprinciples can be used. High loading capacity will be favored by highcharge density in the ionic mineral. A high loading rate is favored bylower molecular weight. Higher ionic mineral concentrations in theloading solution, with a minimum of competing ions, will also favorhigher adsorption capacity.

The amount of ionic mineral that can be loaded onto a resin willtypically range from about 1% to about 70% by weight of the ionicmineral-ion exchange resin particles, preferably about 1 to 50% byweight. A skilled artisan with limited experimentation can determine theoptimum loading for any ionic mineral-resin complex. In one embodiment,loading of about 10% to about 40% by weight, more desirably, about 15%to about 30% by weight, of the ionic mineral-ion exchange resinparticles can be employed. Typical loadings of about 25% by weight ofthe ionic mineral to ion exchange resin particles can be advantageouslyemployed. In one embodiment, e.g., if the amount of ionic mineral isloaded at the lower end of this range, i.e., about 1% to about 15%, orabout 5% to about 10%, or the like, the amount of ionic mineral-ionexchange resin particles in the final formulation can be adjusted toprovide the appropriate effective amount of the ionic mineral. However,this may result in a larger dosage unit, or in the need for increaseddosages to obtain the desired effective amount. In another embodiment,more than one ionic mineral is present in the resin complex. In suchcase, the total amount of ionic minerals is within the ranges providedherein, with each ionic mineral preferably also falling within theseranges.

Typically, the resin is mixed with a suitable diluent in an amount ofabout 1 to 50% w/v of the mixture. In one embodiment, the resin is about5 to about 30% w/w of the mixture. In another embodiment, the resin isabout 10 to 25% w/v of the mixture. In still another embodiment, theresin is about 5 to 10% w/v of the mixture. However, other suitableamounts of the resin may be readily selected.

Typically, the resin is present in an amount of about 30% to about 99%w/w, more preferably about 30% w/w to about 95% w/w, about 60% w/w toabout 90% w/w, or about 85% to about 70% w/w of the ionic mineral-ionexchange resin complex. However, these amounts may be adjusted as neededor desired, if additional components are bound in the ionic mineral-ionexchange resin complex. In one embodiment, no other activepharmaceutical or nutritional ingredients or components are included. Inanother embodiment, another nutritional or pharmaceutically activecomponent is included. In still another embodiment, the active componentis a drug.

In one embodiment, an antioxidant is included in the mixture at the timethe source compound of the ionic mineral is combined with the complexingagent (i.e., resin) in a suitable diluent. In one embodiment, anantioxidant functions to stabilize the ionic mineral. For example, anantioxidant minimizes conversion of ferrous iron to ferric iron, whichis desirable since ferrous iron has been described in the literature asbeing better absorbed by the body. However, even where antioxidant ispresent, some minimal amount of conversation to ferric ion can betolerated.

Typically, an antioxidant is present in amount of about 0.05 to about 2%w/v, and more preferably in an amount of about 0.05 to 0.2% w/v.Suitable antioxidants may be readily selected from among, e.g., ascorbicacid and pharmaceutically acceptable salts thereof, sodiummetabisulfite, sodium bisulfite, sodium sulfite, potassiummetabisulfite, sodium ascorbate, tocopherol, propyl gallate, butylatedhydroxyanisole, butylated hydroxytoluene, edetic acid and its salts. Inone embodiment, the antioxidant is ascorbic acid or a pharmaceuticallyacceptable salt thereof.

The antioxidant may be present in a higher amount. For example, ascorbicacid or a pharmaceutically acceptable salt thereof may be utilized as anantioxidant within the ranges provided herein. Alternatively, theascorbic acid or salt may be present in higher amounts in order toprovide an effective amount of Vitamin C. In this embodiment, theascorbic acid may be present in an amount in excess of 2% w/v, e.g.,about 2.5% w/v to 10% w/v, or about 3.5% to 5% w/v. Following formationof the ionic mineral-ion exchange resin complex in a reaction mixture,antioxidant and diluent may be removed.

Thus, in one aspect, the invention provides ionic mineral-ion exchangeresin complexes comprising an ionic mineral loaded in an ion exchangeresin as described herein.

Finished Dose Formulations

The ionic mineral-ion exchange resin complexes of the present invention,can readily be formulated with pharmaceutically acceptable excipientsaccording to methods well known to those of skill in the art. Indesirable embodiment, the formulations contain an antioxidant. Theformulations of the invention may contain more than one dietarysupplement or another component. For example, the formulation maycontain more than one ionic mineral loaded into an ion exchange resin toform a complex of the invention. As another example, the formulation maycontain a first ionic mineral-ion exchange resin complex of theinvention in combination with another dietary supplement which may be ina second ionic mineral-ion exchange resin complex of the invention. Instill another example, the formulation may contain an ionic mineral-ionexchange resin complex of the invention in combination with one or morecomponents which are not in an ionic mineral-ion exchange resin complex.

The ionic mineral-ion exchange resin complex of the invention may beformulated for delivery by any suitable route including, e.g., orally,intraperitoneally, sublingually, intramuscularly, rectally,transbuccally, intranasally, liposomally, via inhalation, vaginally,intraoccularly, via local delivery (for example, by catheter or stent),subcutaneously, intraadiposally, intraarticularly, or intrathecally.Preferably, the complex is formulated for oral delivery.

The ionic mineral-ion exchange resin composition thus prepared may bestored for future use or promptly formulated with conventionalpharmaceutically acceptable carriers to prepare finished ingestiblecompositions for delivery orally, gastric tube, nasogastric tube, or viaother means. The compositions according to this invention may, forexample, take the form of liquid preparations such as suspensions, orsolid preparations such as capsules, tablets, caplets, sublinguals,powders, wafers, strips, gels, including liquigels, etc. In oneembodiment, a tablet of the invention is formulated as an orallydisintegrating tablet. Such orally disintegrating tablets maydisintegrate in the mouth in less than about 60 seconds.

The ionic mineral-ion exchange resin compositions may be formulatedusing conventional pharmaceutically acceptable carriers or excipientsand well established techniques. In the present invention, ingestiblecarriers are particularly desirable and include liquids and foodproduct. The ionic mineral-ion exchange resins can be mixed with suchingestible liquids or food products, and, optionally used forfortification of pre-packaged liquids and food products. Further,without being limited thereto, such conventional carriers or excipientsinclude aqueous and non-aqueous diluents, binders and adhesives (i.e.,cellulose derivatives and acrylic derivatives), lubricants (i.e.,magnesium or calcium stearate, or vegetable oils, polyethylene glycols,talc, sodium lauryl sulfate, polyoxy ethylene monostearate), thickeners,solubilizers, humectants, disintegrants, colorants, flavorings,stabilizing agents, sweeteners, and miscellaneous materials such asbuffers and adsorbents in order to prepare a particular pharmaceuticalcomposition. The stabilizing agents may include preservatives andanti-oxidants, amongst other components which will be readily apparentto one of ordinary skill in the art. In one embodiment where the ionicmineral is a ferrous-cationic exchange resin complex, the finishedformulation preferably contains an antioxidant which retards oxidationof the ferrous ion to ferric ion. This is desirable due to theabsorption of ferrous iron, as compared to ferric iron.

Suitable thickeners include, e.g., tragacanth; xanthan gum; bentonite;starch; acacia and lower alkyl ethers of cellulose (including thehydroxy and carboxy derivatives of the cellulose ethers). Examples ofcellulose include, e.g., hydroxypropyl cellulose, hydroxypropyl methylcellulose, sodium carboxy methylcellulose, microcrystalline cellulose(MCC), and MCC with sodium carboxyl methyl cellulose. In liquidformulations, such thickening agents may function as suspending agentswhich can be used alone or in combinations. Exemplary suspending agentsmay include starch instant clearjel and xanthan gum. Starch instantclearjel may be used in the amount of from about 0.1 to about 10% w/vand preferably about 2 to about 3% w/v. Xanthan gum is used in theamount of from about 0.01 to about 5% w/v and preferably about 0.1-0.3%w/v. For solid formulations, particularly desirable bulking agentsinclude mannitol and microcrystalline cellulose. Other suitablethickeners, also termed bulking agents, are readily selected fromamongst those components described herein as a cellulose and from thoseknown in the art. Bulking agents may be used alone or in combination inan amount of about 5% w/w to a total amount of up to about 90% w/w,preferably about 10% w/w to a total amount of up to about 70% w/w, morepreferably about 10% w/w to about 50% w/w, most preferably about 10% toabout 30% w/w. In one embodiment, mannitol and/or microcrystallinecellulose may be used in an amount of about 10% w/w to about 15% w/w.When used in combination, they may be present in a ratio of 1:1 w/v orone more be present in a higher amount than another.

The ionic mineral-ion exchange resin compositions may include acomponent which gives the liquid greater viscosity and stability.Suitable components for this purpose include, e.g., glycerin,polyethylene glycol, propylene glycol and mixtures thereof. For example,in one embodiment, a solubilizer may be present in the amount of 1 to50% w/v, and preferably, about 5 to 15% w/v. In one embodiment, thesolubilizer is glycerin.

The oral liquid compositions of the present invention may also compriseone or more surfactants in amounts of up to about 15% w/v, preferablyfrom about 1 to 3% w/v, and more preferably about 0.1 to about 0.5% w/vof the total formulation. The surfactants useful in the preparation ofthe finished compositions of the present invention are generally organicmaterials which aid in the stabilization and dispersion of theingredients in aqueous systems for a suitable homogenous composition.Preferably, the surfactants of choice are non-ionic surfactants such aspoly(oxyethylene)(20) sorbitan monooleate and sorbitan monooleate. Theseare commercially known as TWEENS and SPANS and are produced in a widevariety of structures and molecular weights.

A compound from the group comprising polysorbate copolymers(sorbitan-mono-9-octadecenoate-poly(oxy-1,2-ethanediyl)) can be employedas a surfactant. This compound is also added functions to keep anyflavors and sweeteners homogeneously dissolved and dispersed insolution. Other suitable polysorbates include polysorbate 20,polysorbate 40, polysorbate 80 and mixtures thereof. Most preferably,polysorbate 80 is employed. The surfactant component will comprise fromabout 0.01 to about 2% w/v of the total composition and preferably willcomprise about 0.5 to about 0.6% w/v of the composition.

A second emulsifier/surfactant useful in combination with polysorbatesmay be employed, e.g., a poloxamer such as Poloxamer 407. Poloxamer 407has an HLB (hydrophilic/lipophilic balance) of about 22 and is soldunder the tradename Pluoronic-127 (BASF-NJ). The two surfactants can beemployed in substantially equivalent amounts.

Aqueous suspensions may be obtained by dispersing the ionic mineral-ionexchange resin compositions in a suitable aqueous vehicle, optionallywith the addition of suitable viscosity enhancing agent(s) (e.g.,cellulose derivatives, xanthan gum, etc). Non-aqueous suspensions may beobtained by dispersing the foregoing compositions in a suitablenon-aqueous based vehicle, optionally with the addition of suitableviscosity enhancing agent(s) (e.g., hydrogenated edible fats, aluminumstate, etc.). Suitable non-aqueous vehicles include, for example, almondoil, arachis oil, soybean oil or soybean oil or fractionated vegetableoils such as fractionated coconut oil.

Suitably, a buffer may be included in the vehicle (e.g., purifiedwater). Suitable buffers are well known to those of skill in the art andmay include, e.g., citric acid, tartaric acid, phosphoric acid, aceticacid, and their respective salts. Where utilized, e.g., citric acid, thebuffer may be present in an amount of about 0.1 to 2% w/v, preferablyabout 0.1 to about 0.5% w/v of the composition.

Useful preservatives include, but are not limited to, sodium benzoate,benzoic acid, potassium sorbate, salts of edetate (also known as saltsof ethylenediaminetetraacetic acid, or EDTA, such as disodium EDTA),parabens (e.g., methyl, ethyl, propyl or butyl-hydroxybenzoates, etc.),and sorbic acid. Amongst useful preservatives include chelating agentssome of which are listed above and other chelating agents, e.g.,nitrilotriacetic acid (NTA); ethylenediaminetetracetic acid (EDTA),hydroxyethylethylenediaminetriacetic acid (HEDTA),diethylenetriaminepentaacetic acid (DPTA), 1,2-Diaminopropanetetraaceticacid (1,2-PDTA); 1,3-Diaminopropanetetraacetic acid (1,3-PDTA);2,2-ethylenedioxybis[ethyliminodi(acetic acid)] (EGTA);1,10-bis(2-pyridylmethyl)-1,4,7,10-tetraazadecane (BPTETA);ethylenediamine (EDAMINE);Trans-1,2-diaminocyclohexane-N,N,N′,N′-tetraacetic acid (CDTA);ethylenediamine-N,N′-diacetate (EDDA); phenazine methosulphate (PMS);2,6-Dichloro-indophenol (DCPIP); Bis(carboxymethyl)diaza-18-crown-6(CROWN); porphine; chlorophyll; dimercaprol (2,3-Dimercapto-1-propanol);citric acid; tartaric acid; fumaric acid; malic acid; and salts thereof.The preservatives listed above are exemplary, but each preservative mustbe evaluated in each formulation, to assure the compatibility andefficacy of the preservative. Methods for evaluating the efficacy ofpreservatives in pharmaceutical formulations are known to those skilledin the art. Preferred preservatives are the paraben preservativesinclude, methyl, ethyl, propyl, and butyl paraben. Methyl and propylparaben are most preferable. Preferably, both methyl and propyl parabenare present in the formulation in a ratio of methyl paraben to propylparaben of from about 2.5:1 to about 16:1, preferably 9:1.

In the instance where auxiliary sweeteners are utilized, the presentinvention contemplates the inclusion of those sweeteners well known inthe art, including both natural and artificial sweeteners. Thus,additional sweeteners may be chosen from the following non-limitinglist: Water-soluble sweetening agents such as monosaccharides,disaccharides and polysaccharides such as xylose, ribose, glucose,mannose, galactose, fructose, high fructose corn syrup, dextrose,sucrose, sugar, maltose, partially hydrolyzed starch, or corn syrupsolids and sugar alcohols such as sorbitol, xylitol, mannitol andmixtures thereof;

In general, the amount of sweetener will vary with the desired amount ofsweeteners selected for a particular formulation. This amount willnormally be 0.001 to about 90% by weight, per volume of the finalcomposition, when using an easily extractable sweetener. Depending uponthe selected sweetener, the sweetener is present at the higher end ofthis range for liquid suspensions and at the lower end of the range (orabsent) in solid formulations. The water-soluble sweeteners describedabove, are preferably used in amounts of about 5 to about 80% by weightper volume, and most preferably from about 20 to about 40% by weight pervolume of the final liquid composition. In contrast, the artificialsweeteners [e.g., sucralose, acesulfame K, and dipeptide basedsweeteners] are used in amounts of about 0.005 to about 5.0% w/v, about1-2% w/v, preferably about 0.03 to about 1.1% w/v, more preferably about0.4 to about 0.6% w/v of the final liquid composition, or about 0.2 toabout 0.5% w/w of a solid formulation (e.g., an orally disintegratingtablet). These amounts are ordinarily necessary to achieve a desiredlevel of sweetness independent from the flavor level achieved fromflavor oils.

Suitable flavorings include both natural and artificial flavors, andmints such as peppermint, menthol, artificial vanilla, cinnamon, variousfruit flavors, both individual and mixed, essential oils (i.e. thymol,eucalyptol, menthol and methyl salicylate) and the like arecontemplated. The amount of flavoring employed is normally a matter ofpreference subject to such factors as flavor type, individual flavor,and strength desired. Thus, the amount may be varied in order to obtainthe result desired in the final product. Such variations are within thecapabilities of those skilled in the art without the need for undueexperimentation. The flavorings are generally utilized in amounts thatwill vary depending upon the individual flavor, and may, for example,range in amounts of about 0.01 to about 3% by weight per volume of thefinal composition weight.

The colorants useful in the formulations described herein include thepigments such as titanium dioxide, that may be incorporated in amountsof up to about 1% by weight per volume, and preferably up to about 0.6%by weight per volume. Also, the colorants may include dyes suitable forfood, drug and cosmetic applications, and known as D&C and F.D. & C.dyes and the like. The materials acceptable for the foregoing spectrumof use are preferably water-soluble. Illustrative examples includeindigoid dye, known as F.D. & C. Blue No. 2, which is the disodium saltof 5,5′indigotindisulfonic acid. Similarly, the dye known as F.D. & C.Green No. 1 comprises a triphenylmethane dye and is the monosodium saltof 4-[4-N-ethylp-sulfobenzylamino)diphenylmethylene]-[1-(N-ethyl-N-p-sulfoniumbenzyl)-2,5-cyclohexadienimine]A full recitation of all F.D. & C. and D. & C. and their correspondingchemical structures may be found in the Kirk-Othmer Encyclopedia ofChemical Technology, in Volume 5, at Pages 857-884, which text isaccordingly incorporated herein by reference.

Wetting agents also may be employed in the inventive compositions tofacilitate the dispersion of any hydrophobic ingredients. Theconcentration of wetting agents in the composition should be selected toachieve optimum dispersion of the ingredient within the composition withthe lowest feasible concentration of wetting agent. It should beappreciated that an excess concentration of wetting agent may cause thecomposition, as a suspension, to flocculate. Those skilled in the artare well versed in suitable empirical methods to determine theappropriate wetting agents and concentrations to achieve optimumdispersion and avoid flocculation. Suitable wetting agents are listed inthe US Pharmacoepia 29.

Preparation of Liquid Formulations

In one aspect, a novel method of preparing a liquid formulation usefulas a dietary supplement comprising a non-toxic, orally ingestible,mineral-ion exchange resin complex is provided. This method involvesforming a mixture comprising an ionic mineral compound, apharmaceutically acceptable ion-exchange resin, and the suspension basewhereby a complex comprising the ionic mineral bound to the ion exchangeresin complex is formed in situ. Advantageously, this process eliminatesthe need for isolation of the ionic mineral-resin complex. This permitsall ingredients to be added and processed in the same container,reducing the exposure of the ionic mineral to the risk of oxidation.This process enhances the efficiency of total process time and increasesthe yield due to consolidated processing steps which eliminate the needfor filtration, purification, isolation and drying of the complex into apowder or other dried form. In one particularly desirable embodiment,the wet complex is formulated as a liquid suspension.

In order to form the reaction mixture, a donor compound which is thesource of the ionic mineral is added to a suitable diluent (e.g.,purified water) or another physiologically compatible diluent.Typically, the water is a deionized or purified water. In oneembodiment, an antioxidant and/or a pH adjuster is included in themixture/solution when the ionic mineral source compound is combined withthe resin in the diluent. One example of an antioxidant is ascorbic acidor a pharmaceutically acceptable salt thereof.

Typically, the ion exchange resin complex is added to the solutioncomprising the ionic mineral and optional antioxidant and pH adjusterand the reaction mixture is stirred to allow the ionic mineral-ionexchange resin complex to form. The reaction can be performed at roomtemperature for a period of, e.g., 1 to 4 hours. However, longer orshorter times may be used where desired. In another embodiment, thereaction can be performed temperatures higher than room temperature inorder to increase the rate of the reaction.

Desirable components, including antioxidant, excipients, fluoride, pHadjusters, etc., may be added to the mixture prior to the reactionbetween the donor compound of the ionic mineral and the ion exchangeresin complex, at the same time, or following formation of the complex.In one embodiment, the suspension base is added to the mixture followinga reaction time in which the complex is permitted to form. Optionally,other components such as vitamins, fluoride, omega fatty acids, may beadded to the mixture following formation of the complex, or at the sametime.

In another embodiment, one or more of the components of a suspensionbase may be added to the mixture at substantially the same time as theother components or prior to the formation or completion of the complexformation. Typical components of a suspension base (sometimes termed aplacebo suspension base) include those liquid carriers, flavoringagents, thickeners, preservatives, etc., examples of which are describedherein, which provide desirable taste and suspension properties to afinished orally ingestable, liquid suspension formulation. In thisembodiment, the reaction is generally permitted additional time in orderto permit complex formation.

Optionally, following formation of the ionic mineral-ion exchange resincomplex, the slurry may be rinsed and/or filtered, prior to addition ofthe final suspension base.

In one aspect, a finished formulation contains at least one ionicmineral-ion exchange resin complex, optionally in combination with atleast one selected from amongst minerals, vitamins (e.g., the Vitamin Bfamily, Vitamin K, and Vitamin E, etc.) amino acids, omega fatty acids,a nutrient, or another component.

Suitable amounts of the ionic minerals, vitamins, and like providedherein can be readily determined taking into consideration theseguidelines for the recommended daily intake of each. When used as adietary supplement, a formulation is useful for supplementing thenutrient intake of the diet, and is preferably taken by mouth (orally).Such a formulation may include, in addition to the ionic mineral-ironexchange resin complex, one or more other minerals, vitamins, herbs,botanicals, amino acids, or omega-3-fatty acids, and other componentswhich are not complexed with an ion-exchange resin. Optionally, ionicmineral source compounds and/or uncomplexed ionic mineral from thesource compound, are present in the formulation. Typically, suchuncomplexed ionic mineral and/or ionic mineral source compounds arepresent in trace amounts. Alternatively, the formulations describedherein may contain other uncomplexed compounds comprising ionicminerals, or other uncomplexed ionic minerals. Such compounds may beadded to the formulation during processing, preferably following complexformation.

In one embodiment, at least one ionic mineral-ion exchange resin complexis combined with components selected from one or more of Vitamin C,Vitamin A, Vitamin D, Vitamin B₃, fluoride, folate, folic acid or apharmaceutically salt thereof, sodium, potassium, calcium, omega-3-fattyacids, magnesium, chloride, phosphate, copper, fluoride, iodine, iron,selenium, zinc, boron, chromium, cobalt, germanium, gold, nickel,silver, iodine, molybdenum, platinum, sulfur, tin, and vanadium, amongstothers.

For example, in one embodiment, a composition as described herein maycontain iron in an amount from 0.1 mg to 1500 mg, 1 mg to 1000 mg, 5 mgto 100 mg, or about 10 to 50 mg, or about 15 to 20 mg/dosage unit. Inanother examples, suitable amounts of fluoride may be provided, e.g., bya compound such as sodium fluoride, sodium monofluorophosphate, orstannous fluoride. Examples of suitable amounts of the fluoride mayrange from 0.01 mg/day to 0.5 mg/day for infants to 1 to 3 mg/day forchildren and adults.

Omega-3 fatty acids are polyunsaturated fatty acids classified asessential because they cannot be synthesized in the body; they must beobtained from food. Important omega-3 fatty acids in human nutritionare: α-linolenic acid (ALA), eicosapentaenoic acid (EPA), arachidonicacid (ARA), and docosahexaenoic acid (DHA). Such omega-3 fatty acids arenot assigned recommended daily intakes, but have acceptable daily intakeamounts in the range of about 1.6 grams/day for men and about 1.1grams/day for women.

In one embodiment, a pediatric unit dosage form comprises aferrous-cation exchange resin complex (10 mg/iron), and further providesother components selected one or more of Vitamin A (palmitate) 1000-1700International Units, preferably 1500 IU, Vitamin C (ascorbic acid) 20-50mg, Vitamin B₁ 0.2 to 1, or about 0.4-0.8 mg, Vitamin B₆ (2 to 4 mg),Vitamin B₃ (3-5 mg, preferably 3.3 mg), Iron (ferric ammonium citrate)(2-10 mg, preferably 3.3 mg), Vitamin D₃ 100-500 i.u., Vitamin E₅-10i.u., Vitamin B₆ (0.2 to 2 mg, or about 0.5 to 1 mg), Folic acid (50-1mg, 50 mcg to 75 mcg, or about 65 mcg), Vitamin B₁₂ 1-2 mcg, Iodine 25mcg, Magnesium (chloride) 4.2 mg, Zinc sulfate 3.3 mg, Copper sulfate0.3 mg, Biotin 67 mcg, Vitamin B₅ (1-2 mg), Chlorine (chloride) 10 mg,Inositol (5-10 mg), Potassium (citrate) (5-10 mg), Manganese (sulfate)(0.5-1, preferably 0.8 mg), Vitamin B₁₀ (PABA) (0.25-0.5 mg, preferably0.3 mg), Molybdenum (trioxide) 75-85 mcg), Vandadium (pentoxide) (75-95mcg), Chromium (chloride) (30-35 mcg), and Selenium (sodium selenite)(30-35 mcg), fluoride, 0.25-0.5 mg. These amounts are typicallydelivered in a 1 mL dosage faun and occasionally larger units.

In one embodiment, a liquid suspension containing a ferrous ion-cationresin complex as the active nutritional moiety or active pharmaceuticalingredient, termed interchangeably herein as the “API” is provided. Inone embodiment, the ferrous resin complex is prepared from mixture offerrous sulfate heptahydrate and the cation exchange resin (e.g.,Amberlite IRP-69 resin, anhydrous) in the amount of 5-50% w/v, andpreferably 15-25% w/v in the presence of an ascorbic acid antioxidantwhich is present in a suitable diluent (e.g., purified water) in anamount of 0.05% w/v to 5% w/v, preferably 0.05 to 0.2% w/v. A typicalplacebo base is composed of purified water (or other suitable diluent),anhydrous citric acid buffer (0.1 to 2% w/v, preferably 0.1 to 0.5%w/v), sweeteners including high fructose corn syrup (5-80% w/v,preferably 20-40% w/v) and sucralose (0.03 to 1.1% w/v, preferably 0.4to 0.6% w/v), preservatives such as methylparaben (0.015-0.2% w/v,preferably 0.15-0.2% w/v) and propylparaben (0.01-1% w/v, preferably0.01-0.02% w/v), a solubilizer such as glycerin (1-50% w/v, preferably5-15% w/v), a suspending agents including starch instant clearjel(0.1-10% w/v, preferably 2-3% w/v) and xanthan gum (0.01-5% w/v,preferably 0.1-0.3% w/v), and flavoring (0.1-10% w/v, preferably 1-2%w/v). To form a liquid suspension formulation, the ferrous resin complexis added to the placebo suspension base, to which ascorbic acid in anamount of about 0.01-5% w/v, preferably, 0.01-0.5% w/v, and surfactant(e.g., Polysorbate 80) in an amount of 0.01-15% w/v, preferably about0.1-0.5% w/v.

In another embodiment, a pediatric formulation contains a ferrous-cationexchange resin complex, Vitamin A, Vitamin C, and Vitamin D. Such aformulation may contain 10 mg iron, 1500 IU vitamin A, 35 mg Vitamin C,400 IU Vitamin D. Such a formulation is desirably in the form of aliquid suspension containing polysorbate 80, citric acid, high fructosecorn syrup, sucralose, glycerin, methylparaben, propylparaben, xanathangum, starch instant cleargel, strawberry banana flavor, and water,optionally with dyes such as FD&C yellow #6 and FD&C #40. In oneembodiment, this formulation is an alcohol and sugar-free liquidsuspension which is delivered in a 2 mL daily dose. Optionally, theformulation further contains ferrous sulfate in trace amounts.

In another embodiment, a formulation provides a unit dosage formcomprising an ionic mineral-ion exchange formulation in combination withone or more additional components selected from one or more of thefollowing. The amounts provided following the components are thepresently recommended daily allowances (RDA) for vitamins, orrecommended daily intakes, for certain adult populations unlessotherwise noted. However, it will be readily understood that loweramounts may be selected for inclusion in a formulation. an amount of100% of the currently recommended Vitamin A (3500 IU (29% as BetaCarotene), Vitamin C (60 mg), Vitamin D (400 IU), Vitamin D (400 IU,Vitamin E (30 IU), Vitamin K 25 mcg (this provides 31% RDA), Thiamin 1.5mg, Riboflavin, (1.7 mg), Niacin (20 mg), Vitamin B6 (2 mg), Folic Acid(400 mcg), Vitamin B12 (6 mcg), Biotin (30 mcg), Pantothenic Acid (10mg), Calcium (162 mg provides about 16% of the adult RDA), Iron (18 mg),Phosphorus (109 mg, 11% of RDA), Iodine (150 mcg), Magnesium (100 mgprovides 25% of RDA), Zinc (15 mg), Selenium (20 mcg provides 29% ofRDA), Copper (2 mg), Manganese (2 mg), Chromium (120 mcg), Molybdenum(75 mcg), Chloride (72 mg is 2% RDA), Potassium (80 mg is 2% of RDA).Optional components, for which no daily recommendation allowance isestablished include Boron 150 mcg, Nickel 5 mcg, Silicon 2 mg, Tin 10mcg, Vandadium 10 mcg, Lutein 250 mcg, Lycopene 300 mcg.

In yet another aspect, a formulation adapted for use as a prenatalvitamin is provided. In one embodiment, a formulation contains aniron-cation exchange resin complex, in combination with a folic acid,folate, or other pharmaceutically acceptable salt thereof. Typically,such folic acid or salt thereof is present in an amount of about 50 mcgto about 1 mg), Such a formulation may further contain niacin ornicotinic acid (Vitamin B₃) and/or one or more additional nutrients.

In one embodiment, a dosage unit containing calcium is provided in acalcium-cation exchange mineral resin. Calcium may be provided in anamount of about 100 to about 1500 mg/dose. Typically, for infants, 210mg/day is the RDA. For babies (7 to 12 months), 270 mg/day is the RDA.For children 1 to 3 years, the RDA is 500 mg/day; for 4 to 8 year olds,the RDA is 800 mg/day; for 9 to 13 year olds, the RDA is 1300 mg/day;for 14 to 18 year olds, the RDA is 1300 mg/day; for 19 to 50 year olds,the RDA is 1000 mg/day; for adults over 51, the RDA is 1200 mg/day. Adosage unit may be formulated such that one dosage unit provides theentire recommended daily allowance. Alternatively, it may be formulatedto accommodate two or more dosage units being taken during the day.

Excipients other than those expressly described herein may be readilyselected by one of skill in the art, taking into consideration thedesired formulation. The formulations described herein can be preparedusing the techniques described in this specification, and those whichare well known to those of skill in the art.

Solid Formulations

In another aspect, an ionic mineral-ion exchange resin complexformulated as a tablet is provided. The tablet contains ionicmineral-ion exchange resin complex in an amount of about 10% w/w toabout 90% w/w, more preferably 20% w/w to about 80% w/w, most preferablyabout 25% to about 35% w/w. In one embodiment, the tablet furthercontains bulking materials including mannitol in an amount of 5% w/w to90% w/w, preferably 10% w/w to 15% w/w, and microcrystalline cellulosein an amount of 5% w/w to 90% w/w, preferably 10% w/w to 15% w/w,glidant such as silicon dioxide in an amount of 0.1% w/w to 5% w/w to0.3 w/w to 0.8% w/w, and a disintegrant such as sodium starch glycolatein the amount of 0.2% w/w to 10% w/w.

In another aspect, an ionic mineral-ion exchange resin complexformulated as an orally disintegrating tablet is provided. The tabletcontains ionic mineral-ion exchange resin complex in an amount of about10% w/w to about 90% w/w, more preferably 20% w/w to about 80% w/w, mostpreferably about 25% to about 35% w/w. The tablet may also contain adisintegrating aid such as calcium silicate in the amount of 2% w/w to80% w/w, preferably 6% w/w to 12% w/w, glidant such as silicon dioxide,in the amount of 0.1% w/w to 5% w/w, preferably 0.3% w/w to 0.8% w/w,superdisintegrant such as crospovidone in the amount of 0.5% w/w to 5%w/w, preferably 1% w/w to 2% w/w, bulking materials such as mannitol andmicrocrystalline cellulose in the amounts described for the tabletsabove, and a sweetener such as acesulfame potassium in the amount of0.1% w/w to 5% w/w, preferably 0.2% w/w to 0.5% w/w.

In another aspect, tablets can be formed from the ionic mineral-ionexchange resin complex. Such tablets may include, e.g., a disintegrantand/or a disintegrating aid, and a glidant. In this context,disintegrants are components which facilitate rapid and consistentdisintegration of the tablet in the patient's mouth. These componentsmay be present in the formulation in an amount of from about 0.2% w/w toabout 10% w/w, from about 0.5% w/w to about 5% w/w, from about 0.5% w/wto about 2% w/w, preferably about 1% w/w to about 2% w/w. Examples ofsuitable disintegrants include, e.g., sodium starch glycolate,crospovidone, croscarmellose sodium, low-substituted hydroxypropylcellulose. A disintegrating aid, e.g., calcium silicate, may be presentin the formulation in an amount of about 2% w/w to about 80% w/v,preferably about 5% w/w to about 15% w/w, and more preferably 6% w/w to12% w/w.

A glidant may be present in an amount of about 0.1% w/w to about 5% w/w,and more preferably about 0.3% w/w to about 0.8% w/v. Examples ofsuitable glidants include, e.g., silicon dioxide including colloidalsilicon dioxide, talc, stearic acid, or combinations thereof.

Still other excipients may be readily selected by one of skill in theart, taking into consideration the desired formulation. The formulationsdescribed herein can be prepared using the techniques described in thisspecification, and those which are well known to those of skill in theart.

Uses of the Compositions

In one aspect, a method of delivering an effective amount of an ionicmineral to a subject as a dietary supplement, therapeutic, orprophylactic agent is provided. The compositions described herein areparticularly well suited for daily delivery. However, they may bedelivered more (e.g., 2× or 3×/day), or less frequently (e.g., onalternate days, biweekly, weekly), as needed.

In another aspect, a formulation comprising a complex comprising apharmaceutically effective amount of an ionic mineral component bound toa pharmaceutically acceptable ion exchange resin, and a pharmaceuticallyacceptable carrier. In one embodiment, the iron is delivered in amountsufficient to treat iron deficiency, including, e.g., iron deficiencyanemia. The iron deficiency anemia may be, e.g., antepartum anemia orpost-partum anemia. In one embodiment, a composition for adults containsnon-toxic amounts in excess of the recommended daily allowances for ironprovided above. Alternatively, a formulation providing the recommendeddaily dosage may be delivered, with the frequency of delivery adjusteddepending upon the severity of the iron deficiency.

In another embodiment, a formulation comprising lithium-ion exchangeresin complex can be used to treat mood disorders including, e.g.,bi-polar disorder, mania, and depression. The suggested initial dailydosage for acute mania is 900 to 1800 mg (15 to 20 mg/kg), divided into3 doses. Often, lithium treatment can be started at a dose between 600and 900 mg/day, reaching a level of 1200 to 1800 mg in divided doses onthe second day. Elderly and debilitated patients, and those withsignificant renal impairment should be prescribed lithium withparticular caution. Starting dose should not exceed 300 mg/dayaccompanied by frequent serum level monitoring. Serum concentrations of0.4 to 0.6 mmol/L are usually effective in elderly patients. Inchildren, 0.5 to 1.5 g/m² in divided doses for the acute phase; themaintenance dose should be adjusted to maintain lithium serumconcentrations of 0.5 to 1.2 mmol/L.

Products

In another aspect, a product containing an ionic mineral-ion exchangeresin complex is provided.

In some embodiments, the ionic mineral-ion exchange resin complexes ofthe invention are in packs in a form ready for administration, e.g., ablister pack, a bottle, syringes, foil packs, pouches, or other suitablecontainer. In other embodiments, the compositions described herein arein concentrated form in packs, optionally with the diluent required tomake a final suspension for administration. In still other embodiments,the product contains a compound in solid form and, optionally, aseparate container with a suitable suspension base or other carrier forthe ionic mineral-ion exchange resin complex.

In still other embodiments, the above packs/kits include othercomponents, e.g., a meter dose apparatus/device, instructions fordilution, mixing and/or administration of the product, other containers,nasogastric tubes, etc. Other such pack/kit components will be readilyapparent to one of ordinary skill in the art.

Devices have been described, and many are commercially available, whichprovide for metered administration, including a metered syringe ordispenser cup, and/or metered-dose inhalers. For example, various liquidmetering devices for squeezable bottles have been described [U.S. Pat.No. 6,997,358, U.S. Pat. No. 3,146,919, filed in 1960, U.S. Pat. No.3,567,079, filed in 1968, and in GB 2201395, filed in 1986.] A devicefor dispensing multiple compositions is provided in U.S. Pat. No.6,997,219.

Methods and apparatus for delivery of compositions through nasogastrictubes are well known to those of ordinary skill in the art. See, e.g.,E. Bryson, “Drug Administration via Nasogastric Tube”, Nurs Times, 2001Apr. 19-25 97(16):51. The compositions described herein can be readilydelivered using such devices. Suitable nasogastric tubes are availablecommercially and/or have been described. See, e.g.,

U.S. Pat. No. 5,334,166; U.S. Pat. No. 5,322,073; U.S. Pat. No.4,619,673; U.S. Pat. No. 4,363,323.

EXAMPLES

The following examples are provided to more specifically illustrate thecompositions and are not intended to be limiting. They are forillustrative purposes only and it is realized that changes andvariations can be made without departing from the spirit and scope ofthe invention.

Example 1 illustrates a liquid suspension comprising an ionicmineral-cationic exchange resin complex with the following illustrativeexcipients:

Example 2 illustrates a formulation of the invention containing vitaminsin combination with an ionic mineral-ion exchange resin complex.

Example 3 illustrates a tablet containing a charged mineral-ionicexchange resin complex of the invention using the following illustrativeexcipients.

Example 4 illustrates an orally disintegrating tablet containing acharged mineral-ionic exchange resin complex of the invention in aformulation having the following illustrative excipients.

Examples Example 1 Suspension Formula

Ingredient Quantity Ferrous Resin Complex Ferrous Sulfate Heptahydrate40.91 g Ascorbic Acid 1 g Purified Water 1 L Amberlite IRP-69 Resin(anhydrous) 107 g Placebo Suspension Base Purified Water 1,000 g CitricAcid, anhydrous 8 g FD&C Yellow #6 0.064 g FD&C Red #40 0.144 g HighFructose Corn Syrup 42 1,200 g Methylparaben 7.2 g Propylparaben 0.8 gGlycerin 400 g Sucralose 20 g Starch Instant Clearjel 100.26 g XanthanGum 8.7 g Strawberry/Banana flavor 44.88 g Purified Water QS 3,484 gFerrous Suspension Purified Water 50 g Ascorbic Acid 0.5 g Polysorbate80 0.55 g Ferrous Resin Complex 76.93 g Placebo Suspension base 435.6 gPurified Water QS 500 mL

Process

The ferrous resin complex of this example, Example 1, was prepared byfirst dissolving 1 g of ascorbic acid in 1 L of Purified Water, followedby the addition of 40.91 g of Ferrous Sulfate Heptahydrate withcontinued mixing until dissolved. The Amberlite IRP-69 Resin of 107 gwas then added to the solution and mixed for 4 hours. Upon completion,the slurry was transferred to a laboratory filtration apparatus (PallESF 60) equipped with 10 μm stainless steel screen and filtered underpressure. The residue was further rinsed and filtered with sufficientamount of Purified Water three times. The wet ferrous resin complex wasused for preparing the final suspension.

Placebo suspension base was prepared by dissolving 8 g of citric acid in1,000 g of purified water in the main container, followed by adding1,200 g of high fructose corn syrup. Sucralose (Splenda™) of 20 g wasthen added to the main container and mixed until dissolved. FD&C Yellow#6, and FD&C Red #40 were added to the main container and mixed untildissolved. In a separate container, 400 g of glycerin was added andheated to 45-50° C. before additions of 7.2 g of methylparaben and 0.8 gof propylparaben. After both parabens were dissolved, the solution wascooled to room temperature and 8.7 g of Xanthan gum was uniformlydispersed in it to form the gum dispersion. In the main container,100.26 g of starch instant clearjel was slowly added with the aid ofhigh speed mixing (Silverson mixer) until uniform. The gum dispersionwas then slowly added to the main container and mixed well. The flavorof 44.88 g was then added and QS to 3,484 g with purified water.

The final suspension was prepared by dissolving 0.5 g of ascorbic acidand 0.55 g of polysorbate 80 in 50 g of purified water, followed by theaddition of placebo suspension base, mixed until uniform. The wetferrous resin complex was then slowly introduced to the above solutionunder continuous mixing to achieve uniformity. Purified water was lastadded to adjust the volume to 500 mL and mixed for 15-30 minutes. Thefinal suspension was packaged in 4 oz PET bottles for further stabilityevaluations.

Example 2 Suspension

This example provides a process which eliminates the need for isolationof the Ferrous Resin Complex and which permits all ingredients to beadded and processed in the same container. By forming the complex insitu, this process enhances the efficiency of total process time andincreases the yield due to consolidated processing steps.

Formula

Ingredient Quantity Purified Water 125 g Citric Acid Anhydrous 1 gAscorbic Acid 30 g Sodium Fluoride 0.079 g Ferrous Sulfate Heptahydrate12.45 g Amberlite IRP-60 Resin 37.34 g High Fructose Corn Syrup 42 150 gSucralose 2.5 g FD&C Yellow #6 0.008 g FD&C Red #40 0.018 g Glycerin 50g Methylparaben 0.9 g Propylparaben 0.1 g Polysorbate 80 0.55 g VitaminD 5 mg Vitamin A 0.42 g Xanthan Gum 1.09 g Starch Instant Clearjel 12.54g Strawberry/Banana flavor 5.61 g Purified Water QS 500 mL

Process

The suspension was prepared by first dissolving 1 g of citric acid, 30 gof ascorbic acid and 0.079 g of sodium fluoride in 125 g of PurifiedWater in the main container, followed by the addition of 12.45 g ofFerrous Sulfate Heptahydrate with continued mixing until dissolved. TheAmberlite IRP-69 Resin of 37.34 g was then added to the solution andmixed for 1 hour. In a separate container, 50 g of Glycerin is heated to50° C. before addition of 0.9 of Methylparaben and 0.1 g ofPropylparaben and mixed until dissolved. The solution was cooled to roomtemperature, added 0.55 g of Polysorbate 80 and mixed to dissolved(Glycerin Solution). Vitamin D of 5 mg was then added to the Glycerinsolution, mixed until dissolved followed by 0.42 g of Vitamin A wasslowly dispersed with continuous mixing. The Xanthan Gum of 1.09 g wasthen dispersed into the solution (Gum dispersion). In the maincontainer, High Fructose Corn syrup of 150 g and Sucralose of 2.5 g wereadded and mixed to dissolve. The FD&C Yellow #6 of 0.008 g and FD&C Red#40 of 0.018 g were then added to the main container with continuousmixing until dissolved. Slowly dispersed 12.54 g of Starch InstantClearjel in the main container using high shear mixer (Silverson)followed by adding the Gum Slurry. Upon completion, the product wastransferred to a gentle mixer (VWR) and added 5.61 g Strawberry/BananaFlavor and mixed until uniform. The final volume was adjusted to 500 mLwith Purified Water and mixed for an additional 20-30 minutes. The finalsuspension was packaged in 4 oz PET bottles for further stabilityevaluations.

Example 3 Immediate Release Tablets Formula

Ingredient Quantity Ferrous Resin Complex Ferrous Sulfate Heptahydrate204.55 g Ascorbic Acid 5 g Purified Water 5 L Amberlite IRP-69 Resin 535g Ferrous IR Tablets Ferrous Resin Complex 78.47 g Mannitol 66.67 gMicrocrystalline Cellulose 66.67 g Silicon Dioxide 3.33 g Sodium StarchGlycolate 5 g

Process

The ferrous resin complex was prepared by first dissolving 5 g ofascorbic acid in 5 L of Purified Water, followed by the addition of204.55 g of Ferrous Sulfate Heptahydrate with continued mixing untildissolved. The Amberlite IRP-69 Resin of 535 g was then added to thesolution and mixed for 4 hours. Upon completion, the slurry wastransferred to a laboratory filtration apparatus (Pall ESF 60) equippedwith 10 μm stainless steel screen and filtered under pressure. Theresidue was further rinsed and filtered with sufficient amount ofPurified Water three times. The wet ferrous resin complex was then driedunder ambient condition until the moisture level suitable for tableting.

The powder blend was prepared by adding 78.47 g Ferrous Resin Complex,66.67 g Mannitol, 66.67 g Microcrystalline Cellulose, 3.33 g SiliconDioxide and 5 g Sodium Starch Glycolate to a cube blender (Erweka) andmix for 5 minutes. The powder blend was then removed from the cubeblender and passed through 25 mesh screen, transferred back to the cubeblender and mixed for an additional 3 minutes. The tablets were preparedby transferring the final blend to a tablet press (GlobePharm Mini-PressII) equipped with ⅜″ standard concave tooling and compressed intotablets with a target weight of 472.4 mg and hardness of 5-7 Kp.

Example 4 Orally Disintegrating Tablet—Immediate Release Tablets Formula

Ingredient Quantity Ferrous Resin Complex (from example 3) FerrousSulfate Heptahydrate 40.91 g Ascorbic Acid 1 g Purified Water 1 LAmberlite IRP-69 Resin (anhydrous) 107 g Ferrous ODT IR Tablets FerrousResin Complex 78.47 g Calcium Silicate 46 g Silicon Dioxide 3.33 gMannitol 80 g Microcrystalline Cellulose 66.7 g Crospovidone 6.67 gAcesulfame Potassium 1.67 g

Process

The ferrous resin complex was prepared as shown in example 3. The powderblend was prepared by adding 78.47 g Ferrous Resin Complex, 46 g CalciumSilicate, 3.33 g Silicon Dioxide, 80 g Mannitol, 66.67 gMicrocrystalline Cellulose, 6.67 g Crospovidone and 1.67 g AcesulfamePotassium to a cube blender (Erweka) and mix for 5 minutes. The powderblend was then removed from the cube blender and passed through 25 meshscreen, transferred back to the cube blender and mixed for an additional3 minutes. The tablets were prepared by transferring the final blend toa tablet press (GlobePharm Mini-Press II) equipped with ½″ standardconcave tooling and compressed into tablets with a target weight of848.4 mg and hardness of 4-5 Kp.

All patents, patent publications, and other publications listed in thisspecification are incorporated herein by reference. While the inventionhas been described with reference to a particularly preferredembodiment, it will be appreciated that modifications can be madewithout departing from the spirit of the invention. Such modificationsare intended to fall within the scope of the appended claims.

1. An orally ingestible aqueous iron suspension comprising water, anantioxidant, and a ferrous-ion exchange resin complex which comprisesabout 25% to about 70% by weight ferrous iron based on the weight of theferrous-ion exchange resin complex.
 2. The suspension according to claim1, wherein the antioxidant is present in an amount of about 0.05 toabout 2% w/v.
 3. The iron suspension according to claim 1 which isprepared in situ by the method comprising: (a) combining apharmaceutically acceptable cation exchange resin with an aqueoussolution comprising an antioxidant and a ferrous iron to form an aqueoussuspension; (b) stirring the aqueous suspension for a sufficient amountof time to permit formation of a ferrous-ion exchange resin complexcomprising about 25% to about 70% by weight ferrous iron based on theweight of the ferrous-ion exchange resin complex; (c) optionallycombining one or more additional active components with said aqueoussuspension prior to completion of complex formation; and (d) mixing saidaqueous suspension comprising the ferrous-ion exchange resin complexwith one or more active or inactive components to form the orallyingestible ferrous aqueous suspension, wherein the process is performedin a single container without the need for isolation or drying of themineral-ion exchange resin complex prior to forming the orallyingestible liquid suspension.
 4. The suspension according to claim 3,wherein the antioxidant is present in an amount of about 2.5% w/v toabout 10% w/v in (a).
 5. The suspension according to claim 3, whereinferrous iron combined into the aqueous solution is added in the form offerrous sulfate or a hydrate thereof.
 6. The suspension according toclaim 5, wherein the ferrous iron is ferrous sulfate heptahydrate. 7.The suspension according to claim 1, wherein the antioxidant is selectedfrom one or more of ascorbic acid and pharmaceutically acceptable saltsthereof, butylated hydroxyanisole, butylated hydroxytoluene, sodiummetabisulfite, and sodium bisulfite.
 8. The suspension according toclaim 1 which comprises the ferrous-ion exchange resin complex andbutylated hydroxyanisole.
 9. The suspension according to claim 1 whichfurther comprises one or more vitamins.
 10. The suspension according toclaim 9, wherein the one or more vitamins or nutrients is selected fromthe group consisting of one or more of Vitamin A, niacin, nicotinic aid,folate, folic acid, Vitamin C, Vitamin D, Vitamin K, Vitamin E, and theVitamin B family, and fluoride.
 11. The suspension according to claim 10which comprises Vitamin A and Vitamin D.
 12. The suspension according toclaim 1 which further comprises Vitamin C.
 13. The suspension accordingto claim 1 which further comprises fluoride.
 14. The suspensionaccording to claim 3, wherein the ferrous iron component is mixed withthe ion exchange resin in an amount to allow loading of about 25% toabout 40% by weight, of the iron onto the ion exchange resin.
 15. Thesuspension according to claim 3a, wherein the iron is a ferrous sulfateand the orally ingestible aqueous iron suspension comprising theiron-cation exchange complex further contains ferrous sulfate.
 16. Thesuspension according to claim 1, wherein the ferrous iron is providedfrom a salt or complex selected from the group consisting of ferroussulfate, ferrous fumarate, ferrous polymaltose, ferrous bisglycinate,ferrous glycine sulphate, ferrous gluconate, ferrous citrate, ferrouscarbonate, ferrous lactate, ferrous succinate, ferrous ascorbate, anamino acid ferrous complex, or a hydrate thereof.
 17. The suspensionaccording to claim 3a, wherein ferrous iron is added into a solution inthe form of a salt or complex, which salt or complex is dissolved in anaqueous solution prior to reacting with the ion exchange resin complex.18. The suspension according to claim 1 which further comprises anomega-3-fatty acid component.
 19. An aqueous suspension comprisingwater, an antioxidant comprising butylated hydroxyanisole, a ferrous-ionexchange resin complex which comprises about 25% to about 70% by weightferrous iron based on the weight of the ferrous-ion exchange resincomplex, ferrous sulfate, Vitamin A, Vitamin C, Vitamin D, and fluoride.20. A method of treating iron deficiency comprising the step ofadministering an effective amount of a non-toxic, orally ingestiblemineral-ion exchange resin formulation according to claim 1.